美德三名科学家分享诺贝尔生理学或医学奖

　　新浪科技讯 北京时间10月7日消息，2013诺贝尔生理学或医学奖今日公布，得主为James E. Rothman, Randy W. Schekman & Thomas C. Südhof，得奖原因为他们在细胞内运输机制方面的发现。

　　2013年诺贝尔生理学与医学奖授予的3名科学家，发现了细胞内的运输机制之谜。生物体内每一个细胞都是一个运生产和输出分子的工厂。例如，胰岛素在这里被制造出来并释放进入血液当中，以及神经传递素从一个神经细胞传导至另一个细胞。这些分子在细胞内都是以“小包”的形式传递的，即细胞囊泡。这三位获奖科学家发现了这些“小包”是如何被在正确的时间输运至正确地点的分子机制。

　　Randy Schekman发现了一系列与细胞囊泡输运机制有关的基因。James Rothman则发现了让这些囊泡得以与其目标相融合的蛋白质机制，从而可以实现对所运“货物”的传递。Thomas Südhof则揭示了信号是如何实现对囊泡的控制，使其得以精确分配其所载“货物”。 在这项发现过程中，三位科学家：Rothman, Schekman 和Südhof揭示了细胞内输运体系的精细结构和控制机制。这一系统的失稳将导致有害结果，如神经系统疾病，糖尿病或免疫系统紊乱。

物质是如何传递到细胞内

对于一个庞大且繁忙的港口，需要一套运行体制保证正确的货物在正确的时间运送到正确的地点。细胞，有着被称为细胞器的不同“隔间”，也面临着类似问题：细胞产生分子物质如荷尔蒙、神经传递素、细胞因子、酶等，然后将这些物质在正确的时间里传送到细胞中其他地方或者细胞外。时间和地点决定一切。囊泡体积微小、呈泡状，外面包裹着膜，或在细胞器之间来回运输物质、或与细胞外膜融合将物质释放在外。这一过程十分重要，因为该过程可在有递质的条件下触发神经活动，或在有荷尔蒙的条件下控制代谢。囊泡又如何知道何时何地“发货”呢？

“交通堵塞”揭示遗传控制

Randy Schekman醉心于研究细胞如何组织其运输系统，他在上个世纪70年代决定利用酵母菌作为模型系统来从遗传原理上研究该系统。通过遗传筛查，他发现酵母菌的运输机制有缺陷，其运输系统很差劲，囊泡在细胞的特定区域堆积。他发现导致这种“堵塞”的原因是遗传的，便继续研究，试图找到变异的基因。Schekman发现三类基因能够控制细胞运输系统的不同方面，从而为了解细胞囊泡运输的精密调控机制提供一种新认识。

精确“停靠”

James Rothman同样着迷于研究细胞运输系统的本质。当Rothman在上个世纪80至90年代研究哺乳动物细胞内的囊泡运输时，他发现一种蛋白复合物能让囊泡进入并融合目标膜。在融合过程中，囊泡上的蛋白质与目标膜如同拉链一般相互结合。这样的蛋白质数量很多且只以特定方式结合，如此使得运输物质能够投递到精确位置。同样的原理也在细胞内运行着，当囊泡与细胞外膜结合时便释放其内容物。

后来人们发现，Schekman在酵母菌中发现的基因一部分可编码Rothman在哺乳动物中找到的那些蛋白，从而揭开了这种运输系统的古老进化起源。他们一同绘制出了这种细胞运输机制的关键部分。

时间就是一切
Thomas Südhof对于脑中的神经细胞如何相互交流很感兴趣。信号分子——神经递质从囊泡中释放，通过Rothman和Schekman发现的机制，与神经细胞的外膜融合。不过，只有当神经细胞向其“邻居”发信号时，这些囊泡才被“允许”释放其内容物。这种控制方式为何如此精确?已知的是，钙离子参与其中，在1990年代，Südhof在神经细胞中搜索钙敏感蛋白。他鉴别出这种分子机制，即响应钙离子流入，指导临近蛋白快速将囊泡绑定至神经细胞外膜。“拉链”开启，信号物质释放出来。Südhof的发现解释了短暂的精确如何实现，以及囊泡内容物如何按指令释放。

囊泡运输有助理解疾病过程

三位诺奖得主发现了细胞生理学的一个基础性过程。这些发现对于我们理解“货物”如何以完美的时机和精确性在细胞内外进行转运具有重大的影响。在从酵母到人类的众多有机体中，囊泡运输和融合采用的是相同的原理。这一系统对于众多的生理学过程极为重要，在这些生理学过程中，囊泡融合必须被控制，包括在脑中发信号以及释放荷尔蒙和免疫因子。缺陷性囊泡运输发生于许多疾病中，包括大量神经性和免疫性疾病，以及糖尿病。若是没有这一奇妙的精确组织，细胞将会堕入混乱的深渊。

　　获奖得主简介：

　　James E. Rothman   詹姆斯•罗斯曼

　　美国耶鲁大学细胞生物学系系主任；细胞生物学和化学教授；

James E. Rothman，1950年出生于美国马萨诸塞州Haverhill，他于1976年在哈佛大学医学院获得博士学位，随后在麻省理工学院做博士后研究工作。1978年Rothman前往加州的斯坦福大学，并在那里开始进行针对细胞囊泡的研究工作。Rothman还曾经在普林斯顿大学以及纪念斯隆-凯特林癌症研究所和哥伦比亚大学工作过。2008年，他开始在耶鲁大学任职，目前是耶鲁大学细胞生物学系系主任和教授。

　　教育背景：

　　耶鲁大学，学士学位，1971年

　　哈佛大学，博士学位，1976年

　　麻省理工学院，博士后研究，1976年至1978年

　　主要奖项：

　　2002年获得拉斯克基础医学研究奖；

　　2013年诺贝尔生理学与医学奖

　　Randy Schekman  兰迪•谢克曼

Randy W. Schekman，1948年生于美国明尼苏达州St Paul，曾先后在加州大学洛杉矶分校以及斯坦福大学求学，并于1974年获得博士学位，指导老师为Arthur Kornberg，后者是1959年度诺贝尔奖获得者。1976年，Schekman前往加州大学伯克利分校任职，目前他仍然是该校分子与细胞生物学系教授。同时Schekman也是霍华德休斯医学研究所研究员。

　　加州大学伯克利分校细胞生物学家；2002年因对细胞膜传输的研究获拉斯克基础医学奖； 2013年获诺贝尔生理学或医学奖

　　Thomas C. Südhof  托马斯•居德霍夫

　Thomas C. Südhof，1955年生于德国哥廷根。他在哥廷根大学求学并于1982年获得硕士学位，同年获得该校神经化学博士学位。1983年他前往美国达拉斯的德州大学西南医学研究中心开展博士后研究，其导师是Michael Brown和Joseph Goldstein，他们是1985年度诺贝尔生理学与医学奖得主。Südhof在1991年成为霍华德休斯医学研究所研究员，并在2008年开始担任斯坦福大学分子与细胞生理学教授。

　　1955年生于德国哥廷根，现任职于美国斯坦福大学；2013年获得拉斯科医学奖以及诺贝尔生理学或医学奖

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官网信息：

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Press Release

2013-10-07

The Nobel Assembly at Karolinska Institutet has today decided to award

The 2013 Nobel Prize in Physiology or Medicine

jointly to

James E. Rothman, Randy W. Schekman 
and Thomas C. Südhof

for their discoveries of machinery regulating vesicle traffic, 
a major transport system in our cells

Summary

The 2013 Nobel Prize honours three scientists who have solved the mystery of how the cell organizes its transport system. Each cell is a factory that produces and exports molecules. For instance, insulin is manufactured and released into the blood and chemical signals called neurotransmitters are sent from one nerve cell to another. These molecules are transported around the cell in small packages called vesicles. The three Nobel Laureates have discovered the molecular principles that govern how this cargo is delivered to the right place at the right time in the cell.

Randy Schekman discovered a set of genes that were required for vesicle traffic. James Rothman  unravelled protein machinery that allows vesicles to fuse with their targets to permit transfer of cargo. Thomas Südhof revealed how signals instruct vesicles to release their cargo with precision.

Through their discoveries, Rothman, Schekman and Südhof have revealed the exquisitely precise control system for the transport and delivery of cellular cargo. Disturbances in this system have deleterious effects and contribute to conditions such as neurological diseases, diabetes, and immunological disorders.

How cargo is transported in the cell

In a large and busy port, systems are required to ensure that the correct cargo is shipped to the correct destination at the right time. The cell, with its different compartments called organelles, faces a similar problem: cells produce molecules such as hormones, neurotransmitters, cytokines and enzymes that have to be delivered to other places inside the cell, or exported out of the cell, at exactly the right moment. Timing and location are everything. Miniature bubble-like vesicles, surrounded by membranes, shuttle the cargo between organelles or fuse with the outer membrane of the cell and release their cargo to the outside. This is of major importance, as it triggers nerve activation in the case of transmitter substances, or controls metabolism in the case of hormones. How do these vesicles know where and when to deliver their cargo?

Traffic congestion reveals genetic controllers

Randy Schekman was fascinated by how the cell organizes its transport system and in the 1970s decided to study its genetic basis by using yeast as a model system. In a genetic screen, he identified yeast cells with defective transport machinery, giving rise to a situation resembling a poorly planned public transport system. Vesicles piled up in certain parts of the cell. He found that the cause of this congestion was genetic and went on to identify the mutated genes. Schekman identified three classes of genes that control different facets of the cell´s transport system, thereby providing new insights into the tightly regulated machinery that mediates vesicle transport in the cell.

Docking with precision

James Rothman was also intrigued by the nature of the cell´s transport system. When studying vesicle transport in mammalian cells in the 1980s and 1990s, Rothman discovered that a protein complex enables vesicles to dock and fuse with their target membranes. In the fusion process, proteins on the vesicles and target membranes bind to each other like the two sides of a zipper. The fact that there are many such proteins and that they bind only in specific combinations ensures that cargo is delivered to a precise location. The same principle operates inside the cell and when a vesicle binds to the cell´s outer membrane to release its contents.

It turned out that some of the genes Schekman had discovered in yeast coded for proteins corresponding to those Rothman identified in mammals, revealing an ancient evolutionary origin of the transport system. Collectively, they mapped critical components of the cell´s transport machinery.

Timing is everything

Thomas Südhof was interested in how nerve cells communicate with one another in the brain. The signalling molecules, neurotransmitters, are released from vesicles that fuse with the outer membrane of nerve cells by using the machinery discovered by Rothman and Schekman. But these vesicles are only allowed to release their contents when the nerve cell signals to its neighbours. How is this release controlled in such a precise manner? Calcium ions were known to be involved in this process and in the 1990s, Südhof searched for calcium sensitive proteins in nerve cells. He identified molecular machinery that responds to an influx of calcium ions and directs neighbour proteins rapidly to bind vesicles to the outer membrane of the nerve cell. The zipper opens up and signal substances are released. Südhof´s discovery explained how temporal precision is achieved and how vesicles´ contents can be released on command.

Vesicle transport gives insight into disease processes

The three Nobel Laureates have discovered a fundamental process in cell physiology. These discoveries have had a major impact on our understanding of how cargo is delivered with timing and precision within and outside the cell.  Vesicle transport and fusion operate, with the same general principles, in organisms as different as yeast and man. The system is critical for a variety of physiological processes in which vesicle fusion must be controlled, ranging from signalling in the brain to release of hormones and immune cytokines. Defective vesicle transport occurs in a variety of diseases including a number of neurological and immunological disorders, as well as in diabetes. Without this wonderfully precise organization, the cell would lapse into chaos.

 

James E. Rothman was born 1950 in Haverhill, Massachusetts, USA. He received his PhD from Harvard Medical School in 1976, was a postdoctoral fellow at Massachusetts Institute of Technology, and moved in 1978 to Stanford University in California, where he started his research on the vesicles of the cell. Rothman has also worked at Princeton University, Memorial Sloan-Kettering Cancer Institute and Columbia University. In 2008, he joined the faculty of Yale University in New Haven, Connecticut, USA, where he is currently Professor and Chairman in the Department of Cell Biology.

Randy W. Schekman was born 1948 in St Paul, Minnesota, USA, studied at the University of California in Los Angeles and at Stanford University, where he obtained his PhD in 1974 under the supervision of Arthur Kornberg (Nobel Prize 1959) and in the same department that Rothman joined a few years later. In 1976, Schekman joined the faculty of the University of California at Berkeley, where he is currently Professor in the Department of Molecular and Cell biology. Schekman is also an investigator of Howard Hughes Medical Institute.

Thomas C. Südhof was born in 1955 in Göttingen, Germany. He studied at the Georg-August-Universität in Göttingen, where he received an MD in 1982 and a Doctorate in neurochemistry the same year. In 1983, he moved to the University of Texas Southwestern Medical Center in Dallas, Texas, USA, as a postdoctoral fellow with Michael Brown and Joseph Goldstein (who shared the 1985 Nobel Prize in Physiology or Medicine). Südhof became an investigator of Howard Hughes Medical Institute in 1991 and was appointed Professor of Molecular and Cellular Physiology at Stanford University in 2008.

 

Key publications:

Novick P, Schekman R: Secretion and cell-surface growth are blocked in a temperature-sensitive mutant of Saccharomyces cerevisiae. Proc Natl Acad Sci USA 1979; 76:1858-1862.

Balch WE, Dunphy WG, Braell WA, Rothman JE: Reconstitution of the transport of protein between successive compartments of the Golgi measured by the coupled incorporation of N-acetylglucosamine. Cell 1984; 39:405-416.

Kaiser CA, Schekman R: Distinct sets of SEC genes govern transport vesicle formation and fusion early in the secretory pathway. Cell 1990; 61:723-733.

Perin MS, Fried VA, Mignery GA, Jahn R, Südhof TC: Phospholipid binding by a synaptic vesicle protein homologous to the regulatory region of protein kinase C. Nature 1990; 345:260-263.

Sollner T, Whiteheart W, Brunner M, Erdjument-Bromage H, Geromanos S, Tempst P, Rothman JE: SNAP receptor implicated in vesicle targeting and fusion. Nature 1993;  362:318-324.

Hata Y, Slaughter CA, Südhof TC: Synaptic vesicle fusion complex contains unc-18 homologue bound to syntaxin. Nature 1993; 366:347-351.

 

Image (pdf 197 Kb) 

 

The Nobel Assembly, consisting of 50 professors at Karolinska Institutet, awards the Nobel Prize in Physiology or Medicine. Its Nobel Committee evaluates the nominations. Since 1901 the Nobel Prize has been awarded to scientists who have made the most important discoveries for the benefit of mankind.

Nobel Prize® is the registered trademark of the Nobel Foundation

诺贝尔得主的主要文献，从文章来看，三位得奖者也曾有过密切合作：

James E. Rothman代表性文章

Gao Y, Zorman S, Gundersen G, Xi Z, Ma L, Sirinakis G, Rothman JE, Zhang Y.Single reconstituted neuronal SNARE complexes zipper in three distinct stages.Science. 2012 Sep 14;337(6100):1340-3.

Shi L, Shen QT, Kiel A, Wang J, Wang HW, Melia TJ, Rothman JE, Pincet F.SNARE proteins: one to fuse and three to keep the nascent fusion pore open.Science. 2012 Mar 16;335(6074):1355-9. 

Südhof TC, Rothman JE.Membrane fusion: grappling with SNARE and SM proteins.Science. 2009 Jan 23;323(5913):474-7.

Shen J, Tareste DC, Paumet F, Rothman JE, Melia TJ.Selective activation of cognate SNAREpins by Sec1/Munc18 proteins.Cell. 2007 Jan 12;128(1):183-95

Giraudo CG, Eng WS, Melia TJ, Rothman JE.A clamping mechanism involved in SNARE-dependent exocytosis.Science. 2006 Aug 4;313(5787):676-80 

Burri L, Varlamov O, Doege CA, Hofmann K, Beilharz T, Rothman JE, Söllner TH, Lithgow T. A SNARE required for retrograde transport to the endoplasmic reticulum.Proc Natl Acad Sci U S A. 2003 Aug 19;100(17):9873-7 

Hu C, Ahmed M, Melia TJ, Söllner TH, Mayer T, Rothman JE. Fusion of cells by flipped SNAREs.Science. 2003 Jun 13;300(5626):1745-9

Rothman JE.Lasker Basic Medical Research Award. The machinery and principles of vesicle transport in the cell. Nat Med. 2002 Oct;8(10):1059-62

Parlati F, Varlamov O, Paz K, McNew JA, Hurtado D, Söllner TH, Rothman JE.Distinct SNARE complexes mediating membrane fusion in Golgi transport based on combinatorial specificity.Proc Natl Acad Sci U S A. 2002 Apr 16;99(8):5424-9

Randy W. Schekman 主要代表性文章
Schekman RW.Retrospective: George E. Palade (1912-2008). Science. 2008 Oct 31;322(5902):695.

Kim J, Kleizen B, Choy R, Thinakaran G, Sisodia SS, Schekman RW.Biogenesis of gamma-secretase early in the secretory pathway. J Cell Biol. 2007 Dec 3;179(5):951-63

Valdivia RH, Baggott D, Chuang JS, Schekman RW.The yeast clathrin adaptor protein complex 1 is required for the efficient retention of a subset of late Golgi membrane proteins. Dev Cell. 2002 Mar;2(3):283-94

Thomas C. Südhof  主要代表性文章(仅Cell, Nature, Science上文章就接近30篇）

Aoto J, Martinelli DC, Malenka RC, Tabuchi K, Südhof TC.Presynaptic neurexin-3 alternative splicing trans-synaptically controls postsynaptic AMPA receptor trafficking.Cell. 2013 Jul 3;154(1):75-88.

Burré J, Vivona S, Diao J, Sharma M, Brunger AT, Südhof TC.Properties of native brain α-synuclein.Nature. 2013 Jun 13;498(7453):E4-6; discussion E6-7.

Xu W, Südhof TC.A neural circuit for memory specificity and generalization.Science. 2013 Mar 15;339(6125):1290-5.

Rizo J, Südhof TC.The membrane fusion enigma: SNAREs, Sec1/Munc18 proteins, and their accomplices--guilty as charged?Annu Rev Cell Dev Biol. 2012;28:279-308.

Pang ZP, Yang N, Vierbuchen T, Ostermeier A, Fuentes DR, Yang TQ, Citri A, Sebastiano V, Marro S, Südhof TC, Wernig M.Induction of human neuronal cells by defined transcription factors.Nature. 2011 May 26;476(7359):220-3.

Cao P, Maximov A, Südhof TC.Activity-dependent IGF-1 exocytosis is controlled by the Ca(2+)-sensor synaptotagmin-10.Cell. 2011 Apr 15;145(2):300-11.

Kaeser PS, Deng L, Wang Y, Dulubova I, Liu X, Rizo J, Südhof TC.RIM proteins tether Ca2+ channels to presynaptic active zones via a direct PDZ-domain interaction. Cell. 2011 Jan 21;144(2):282-95.

Burré J, Sharma M, Tsetsenis T, Buchman V, Etherton MR, Südhof TC.Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro.Science. 2010 Sep 24;329(5999):1663-7.

Vierbuchen T, Ostermeier A, Pang ZP, Kokubu Y, Südhof TC, Wernig M.Direct conversion of fibroblasts to functional neurons by defined factors.Nature. 2010 Feb 25;463(7284):1035-41
 
Zhang C, Wu B, Beglopoulos V, Wines-Samuelson M, Zhang D, Dragatsis I, Südhof TC, Shen J.Presenilins are essential for regulating neurotransmitter release.Nature. 2009 Jul 30;460(7255):632-6.

Maximov A, Tang J, Yang X, Pang ZP, Südhof TC.Complexin controls the force transfer from SNARE complexes to membranes in fusion.Science. 2009 Jan 23;323(5913):516-21. 

Südhof TC, Rothman JE.Membrane fusion: grappling with SNARE and SM proteins.Science. 2009 Jan 23;323(5913):474-7.

Südhof TC.Neuroligins and neurexins link synaptic function to cognitive disease.Nature. 2008 Oct 16;455(7215):903-11. 

Gerber SH, Rah JC, Min SW, Liu X, de Wit H, Dulubova I, Meyer AC, Rizo J, Arancillo M, Hammer RE, Verhage M, Rosenmund C, Südhof TC.Conformational switch of syntaxin-1 controls synaptic vesicle fusion.Science. 2008 Sep 12;321(5895):1507-10.

Mukherjee K, Sharma M, Urlaub H, Bourenkov GP, Jahn R, Südhof TC, Wahl MC.CASK Functions as a Mg2+-independent neurexin kinase.Cell. 2008 Apr 18;133(2):328-39

Sun J, Pang ZP, Qin D, Fahim AT, Adachi R, Südhof TC.A dual-Ca2+-sensor model for neurotransmitter release in a central synapse.Nature. 2007 Nov 29;450(7170):676-82

Tabuchi K, Blundell J, Etherton MR, Hammer RE, Liu X, Powell CM, Südhof TC.A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science. 2007 Oct 5;318(5847):71-6

Südhof TC.Synaptic vesicles: an organelle comes of age.Cell. 2006 Nov 17;127(4):671-3.

Tang J, Maximov A, Shin OH, Dai H, Rizo J, Südhof TC.A complexin/synaptotagmin 1 switch controls fast synaptic vesicle exocytosis.Cell. 2006 Sep 22;126(6):1175-87.

Chandra S, Gallardo G, Fernández-Chacón R, Schlüter OM, Südhof TC. Alpha-synuclein cooperates with CSPalpha in preventing neurodegeneration.Cell. 2005 Nov 4;123(3):383-96

Sudhof TC.The synaptic vesicle cycle.Annu Rev Neurosci. 2004;27:509-47.

Lonart G, Schoch S, Kaeser PS, Larkin CJ, Südhof TC, Linden DJ.Phosphorylation of RIM1alpha by PKA triggers presynaptic long-term potentiation at cerebellar parallel fiber synapses.Cell. 2003 Oct 3;115(1):49-60

Missler M, Zhang W, Rohlmann A, Kattenstroth G, Hammer RE, Gottmann K, Südhof TC.Alpha-neurexins couple Ca2+ channels to synaptic vesicle exocytosis.Nature. 2003 Jun 26;423(6943):939-48

Jahn R, Lang T, Südhof TC.Membrane fusion.Cell. 2003 Feb 21;112(4):519-33.

Biederer T, Sara Y, Mozhayeva M, Atasoy D, Liu X, Kavalali ET, Südhof TC.SynCAM, a synaptic adhesion molecule that drives synapse assembly.Science. 2002 Aug 30;297(5586):1525-31

Castillo PE, Schoch S, Schmitz F, Südhof TC, Malenka RC.RIM1alpha is required for presynaptic long-term potentiation.Nature. 2002 Jan 17;415(6869):327-30.

Rhee JS, Betz A, Pyott S, Reim K, Varoqueaux F, Augustin I, Hesse D, Südhof TC, Takahashi M, Rosenmund C, Brose N. Beta phorbol ester- and diacylglycerol-induced augmentation of transmitter release is mediated by Munc13s and not by PKCs.Cell. 2002 Jan 11;108(1):121-33

Schoch S, Castillo PE, Jo T, Mukherjee K, Geppert M, Wang Y, Schmitz F, Malenka RC, Südhof TC.RIM1alpha forms a protein scaffold for regulating neurotransmitter release at the active zone.Nature. 2002 Jan 17;415(6869):321-6